AIDS is the leading cause of death in men between the ages of 25 and 44 in 60% of cities in the United States. Initial work on the disease centered on the search for a causative agent, and a critical step in the understanding of AIDS came with the discovery of the retroviral basis of the disease by Gallo, et al. (Science, 220:865-868 (1983)) and Montagnier (Barre-Sinoussi, et al. Science 220:868-71 (1983)).
Retroviruses are simple structures which utilize RNA as their genetic material. In order to complete its life cycle, the retrovirus must first enter a cell, where the retrovirus then uses its RNA as a template for the synthesis of DNA. To accomplish this synthesis of genetic material which ultimately results in the formation of new viral cells, the virus encodes a unique protein, RNA dependent DNA polymerase (reverse transcriptase). Since this enzyme is not found in eukaryotic cells, reverse transcriptase is an obvious target for drugs which could disrupt replication of the AIDS virus without affecting cellular processes, and indeed much of the research into treatments for retroviral ailments such as AIDS has focused on the inhibition of the synthesis of DNA by reverse transcriptase.
The retrovirus which causes AIDS is human immunodeficiency virus ("HIV"). HIV is part of a group of lentiviruses, or slow viruses, which cause diseases which develop extremely slowly. In some HIV-infected patients, for example, symptoms of AIDS do not appear for 10 years or more. HIV undergoes different types of cycles in depending upon the type of cell infected. The major cells infected by HIV, however, are those of the immune system which contain the antigen CD4 on their cell surfaces. These cell types include T.sub.helper cells and macrophages. In the T.sub.helper cells, the virus undergoes a lytic cycle in which replication of the virus ultimately leads to lysis of the cells. Since T.sub.helper cells play a critical role in both humoral and cellular immunity, destruction of these cells compromises both aspects of the immune system. In macrophages, on the other hand, HIV generally undergoes a non-lytic behavior in which viral particles are produced, but at relatively low levels. In this type of cell, a "latent state" of viral infection is observed, and it is therefore believed that the macrophages are the main reservoir of the retrovirus in the patient.
The first agent approved by the FDA for the treatment of AIDS was azidothymidine (AZT). AZT, an analog of thymidine, is incorporated into the growing DNA strand during synthesis by the viral reverse transcriptase. Its incorporation prevents further synthesis of the DNA strand, and therefore interferes with viral replication. Other drugs such as dideoxyinosine (DDI) inhibit HIV replication in a similar fashion. While drugs such as AZT and DDI have been shown to be effective in slowing the progress of the disease, both produce significant side effects. In particular, these compounds can be incorporated into cellular DNA, leading to interference with normal cellular function. Thus, there is a need for drugs which are incapable of being incorporated into cellular DNA for use either alone or in combination with other treatments.
Gold-based drugs have been used for over 100 years for the treatment of several diseases. In the 19th century, gold cyanide was used for the treatment of tuberculosis, while more recently the primary use of gold drugs has been in the treatment of rheumatoid arthritis. The principal drugs currently used for inducing remission in rheumatoid arthritis are sodium gold(I) thiomalate (Myochrysine), gold(I) thioglucose (Solganol), and triethylphosphinegold(I)tetraacetylthioglucose (Auranofin). Although the therapeutic mechanism of these drugs has not been clearly established, numerous possibilities have been suggested. These include interference with copper metabolism, inhibition of lysosomal enzymes such as collagenase, and interference with steroid metabolism (Sadler, P., Adv. Inorg. Chem. 36:1-48 (1991)). Other theories involve the modification of cellular activities, including cellular transport functions, through the interaction of thiol groups on the membrane. Such modifications may also include a modulation of the lymphocyte activation observed in arthritis (Smith, W. E. and J. Reglinski, Persp. Inorg. Chem. 1:183-208 (1991)). Recently, gold-based drugs, particularly Auranofin, have also been used to treat asthma and psoriasis. This long history of the use of gold-based drugs has also shown that they are well-tolerated by patients, and a considerable amount of information on tolerance levels is available.
While there have been suggestions that certain gold-based drugs may be effective in treating AIDS, none have been proven to be effective. PCT/FR90/00387, for example, suggests that gold(I) thiol complexes, including gold(I)thioglucose (Solganol), inhibit HIV reverse transcriptase in in vitro assays. The relevance of this information for the treatment of HIV infection is questionable, since viral replication of HIV within an infected host takes place within the target cells. Gold thioglucose, however, is inherently unable to enter cells, and it consequently does not have access to the reverse transcriptase. The proposed route for overcoming this problem is the introduction of the gold compound through the use of liposomes to permit specific delivery to target cells. The effectiveness of such a delivery system, however, has not been demonstrated.
More recently, it has been demonstrated that gold(I) complexes such as bis(thioglucose)gold(I)inhibit the infectivity of HIV in the lymphoblastic leukemia cell line CEM in a cell culture. Although the compound does inhibit HIV reverse transcriptase in an in vitro system, the primary effect of the compound is claimed to be at the level of the gp40 antigen on the cell surface. Binding of HIV requires gp120, which is attached to the cell surface through gp40. Interference with the glycoprotein interaction prevents attachment of the virus to the potentially susceptible cell. While these experiments show a significant effect of bis(thioglucose)gold(I) on HIV infection in vitro, the cell culture system in which they were carried out permits concentrations of the compound in the 6ppm range. Such a level, however, is significantly higher than concentrations routinely found in the bloodstream of patients treated with gold-based drugs, and may very well be a toxic level for most people.
Thus, while it has been suggested that certain gold-based drugs may be effective in treating AIDS, none have been proven in in vivo studies. More importantly, some of these proposals would intuitively appear to be ineffective because of the current understanding of AIDS and gold-based drugs.